Crystalline forms of (s)-afoxolaner

ABSTRACT

The present invention provides crystalline forms of compound of formula (Ia) and processes of making the crystalline forms. Also provided are compositions comprising the crystalline forms and methods of use of the crystalline forms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/482,175, filed Apr. 5, 2017, which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present disclosure generally relates to solid forms of compound offormula (Ia)

BACKGROUND OF THE INVENTION

Polymorphs can differ in such physical and chemical (i.e.physiochemical) properties as crystal shape, density, hardness, color,chemical stability, melting point, hygroscopicity, suspendability anddissolution rate, and such biological properties as biologicalavailability. Predicting physiochemical properties for a crystal form orcrystal forms in which the solid state of a chemical compound can existremains impossible.

Also, the single enantiomers of pharmacologically active compounds havemet an increased interest in the last years because of improvedpharmacokinetic and biological properties. Therefore, there is a needfor a process that can be used in large scale for the preparation of thesingle enantiomers of afoxolaner. Generally, asymmetric processes forobtaining chiral molecules afford optically active molecules inenantiomerically enriched forms rather than in pure single enantiomericforms unless the processes include resolution methods. Therefore, thereis also a need for a method that can be used in large scale for theenhancement of enantiomeric purity of optically active (S)-afoxolaner.

Afoxolaner may exist as two enantiomeric configurations, namely the(S)-enantiomer which is the compound of formula (Ia):

and the (R)-enantiomer, which is a compound of formula (Ib):

Furthermore, even predicting whether the solid state of a compound maybe present in more than one crystal form is not possible.

U.S. Patent Application No. 62/319,207, which is the priority documentfor U.S. patent application Ser. No. 15/480,316 published as US2017/0311601 A1 (all incorporated herein by reference) discloses acompound of formula (Ia) and methods for its preparation, as well as theutility of this compound as an invertebrate pest control agent. Newsolid forms of this compound have now been discovered.

U.S. Pat. No. 8,410,153, incorporated herein by reference, describesafoxolaner as being effective in treating or preventing parasiticinfections or infestations in or on animals.

INCORPORATION BY REFERENCE

Any foregoing applications and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.Citation or identification of any such document in this application isnot an admission that such document is available as prior art to thepresent invention.

SUMMARY OF THE INVENTION

This invention relates to solid forms of compound of formula (Ia). Moreparticularly, this invention is directed to crystalline forms of thecompound of formula (Ia) designated Form I and Form II and for processesto prepare these crystalline forms.

This invention also relates to compositions containing solid forms ofcompound of formula (Ia) and methods for controlling an invertebratepest comprising contacting the invertebrate pest or its environment witha biologically effective amount of a solid form of compound of formula(Ia) or a composition containing a solid form of compound of formula(Ia).

The invention in its particular features will become more apparent fromthe following detailed description considered with reference to theaccompanying examples. The following description will continue todiscuss the problems and solutions offered by the present invention asthey pertain to antiparasitic applications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of crystalline Form I ofcompound of formula (Ia) showing absolute intensity count graphedagainst 2θ reflection positions.

FIG. 2 shows a differential scanning calorimetry thermogram ofcrystalline Form I of compound of formula (Ia).

FIG. 3 shows a powder X-ray diffraction pattern of crystalline Form IIof compound of formula (Ia) showing absolute intensity count graphedagainst 2θ reflection positions.

FIG. 4 shows a differential scanning calorimetry thermogram ofcrystalline Form II of compound of formula (Ia).

DETAILED DESCRIPTION OF THE INVENTION

The term “about,” as used herein, means approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%. Therefore, about 50% means in therange of 45%-55%. Numerical ranges recited herein by endpoints includeall numbers and fractions subsumed within that range (e.g. 1 to 5includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to beunderstood that all numbers and fractions thereof are presumed to bemodified by the term “about.”

The term “administering” as used herein refers to any method which, insound veterinary practice delivers the compound or compositions used inthis invention to the subject to be treated in such a manner so as to beeffective in the prevention or treatment of a parasitic infestation. Forexample, the compound or composition is administered via oral,parenteral, percutaneous or topical routes. Topical administrationcomprises, in particular, skin solutions (pour-on or spot-on), sprays,baths, showers, jets, powders, greases, shampoos, creams, etc. Thepour-on type skin solutions may be designed for percutaneous delivery orfor distribution of the active on the exterior of the animal.

The term “anhydrate” or “anhydrous polymorph” or “anhydrous crystallineform” refers to a crystalline form that does not have water bound in thecrystal lattice. However, the crystals may contain trace amount of wateror other solvents not bound in the crystal lattice.

The term “amorphous” as applied to afoxolaner herein refers to a solidstate wherein the afoxolaner molecules are present in a disorderedarrangement and do not form a distinguishable crystal lattice or unitcell. When subjected to X-ray powder diffraction, amorphous afoxolanerdoes not produce any characteristic crystalline peaks.

The term “chemical purity” refers to the overall level of a desiredproduct. If a compound is present in enantiomeric forms, “chemicalpurity” as used herein would include both enantiomeric forms in thecalculation of the overall level of the desired product. If a compoundis present in solvate forms, “chemical purity” as used herein wouldinclude the solvate in the calculation of the overall level of thedesired product. Impurities may be in the form of, for example, thepresence of unwanted process reagents, process intermediates,degradation products or oxidation products. In particular embodimentsthe chemical purity is high, that is greater than 90% chemical purity,especially above 92.5%, 95%, 96%, 97%, 98%, 99%, 99.9% and includes100%. The purity may be measured a variety of techniques, including HPLCanalysis.

The term “effective amount” as used herein refers to a sufficient amountof the crystalline form of the compound of formula (Ia) to eradicate orreduce the number of parasites infesting the animal. In someembodiments, an effective amount of the active agent achieves at least70% efficacy against the target parasite. In other embodiments, aneffective amount of the crystal form of the invention achieves at least80%, or at least 90% efficacy against the target pests. Preferably, aneffective amount of the crystal form of the invention will achieve atleast 95%, at least 98% or 100% efficacy against the target parasites.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight, to the same degree, in the opposite direction.

The term “enantiomeric excess” or “e.e.” as used herein refers to adifference between the amount of one enantiomer and the amount of theother enantiomer that is present in the product mixture. Theenantiomeric excess value in each example given below gives anindication of the relative amount of each enantiomer. The value isdefined as the difference between the relative percentages for the twoenantiomers. Thus, for example, when the percentage of the(S)-enantiomer of the compound of the invention is 97.5% and thepercentage for the (R)-enantiomer is 2.5%, the enantiomeric excess forthe (S)-enantiomer is 95%.

The terms “enantiomerically pure” or “enantiomeric purity” as usedherein is a measure of how much more of one enantiomer there is than theother enantiomer in a mixture of enantiomers. For example, a mixture of99% (S)-enantiomer and 1% (R)-enantiomer has 99% enantiomeric purity ofthe (S)-enantiomer. Enantiomerically pure is preferably at least 95% orat least 98% enantiomeric purity, more preferably at least about 99%. Inanother embodiment enantiomerically is about 99.90% to about 100%enantiomeric purity.

The term “isolated” as used herein, in reference to solid state forms ofafoxolaner of the present disclosure corresponds to a solid state formof afoxolaner that is physically separated from the solution in which itis formed.

The term “volume of solvent” as used herein refers to the volume ofsolvent, expressed in liters at ambient temperature, used in a processto dissolve 1 kg of solid material. For example 5 volumes of solventused in a process starting with 1 kg of starting material would equal 5liters of solvent.

As used herein, a “lower alkyl alcohol” refers to a branched orstraight-chained C₁-C₆ alkyl group containing one hydroxy group, such asethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, sec-butylalcohol, t-butyl alcohol, pentanol, hexanol, etc; with preferred loweralkyl alcohols including ethanol, propanol and isopropanol; mostpreferably ethanol.

As used herein, an “aliphatic solvent” refers to a linear, branched orcyclic aliphatic solvent containing up to 9 carbon atoms. Aliphaticsolvents include alkane, alkene or alkyne solvents. Non-limitingexamples of aliphatic solvents include pentane, hexane, heptane, octane,cyclopentane, cyclohexane, and the like.

The term “non-solvate polymorph” or “non-solvate crystalline form”refers to a crystalline form that does not have a solvent bound in thecrystal lattice, for example an anhydrous polymorph. However, thecrystals may contain trace amount of solvent not bound in the crystallattice.

The term “or” as used herein, and unless expressly stated to thecontrary, refers to an inclusive or and not to an exclusive or. Forexample, a condition A or B is satisfied by any one of the following: Ais true (or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

The term “pharmaceutically acceptable carrier” as used herein, mayinclude any and all solvents, diluents, or other liquid or solidvehicles, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Eighteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa. 1990) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compound (Ia) suchas by producing any undesirable biological effect or otherwiseinteracting in a deleterious manner with any other component(s) of thepharmaceutical composition, its use is contemplated to be within thescope of this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil, sesame oil; olive oil; corn oil and soybean oil; glycerin, glycerinesters, glycols; such as propylene glycol or polyethylene glycol; esterssuch as ethyl oleate and ethyl laurate; agar, buffering agents such asmagnesium hydroxide and aluminum hydroxide; alginic acid; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

The term “polymorph”, as used herein, refers to the different crystalstructures (of solvated or non-solvated forms) in which a compound cancrystallize.

The term “racemic” or “racemate”, and other like terms refer togenerally equimolar proportions of a (S)-afoxolaner and a(R)-afoxolaner.

The term “seed” as used herein can be used as a noun to describe one ormore crystals of crystalline afoxolaner (e.g., polymorph Form I). Forexample, if it is desired to produce crystalline (S)-afoxolanerpolymorph Form I, the seed crystals to be used to enhance thecrystallization process can be crystals of (S)-afoxolaner polymorph FormI. The term “seed” or “seeding” can also be used as a verb to describethe act of introducing said one or more crystals of a afoxolaner (e.g.,polymorph Form I) into an environment (including, but not limited toe.g., a solution, a mixture, a suspension, or a dispersion) therebyresulting in the formation of more of the same crystals of afoxolaner(e.g., polymorph Form I).

The term “solvate”, “solvate polymorph” or “solvate crystalline form”refers to a crystalline form that has solvate bound in the crystallattice.

The phrase “substantially pure crystal form”, unless otherwise specifiedis to be understood as a substance free of other crystal forms, oramorphous form, at amounts detectable with typical analytical methodssuch as X-ray powder diffraction and/or solid state infrared absorption,i.e. containing less than 10% of other crystal forms. Preferably, thereis less than 5%, more preferably less than 2%, and even more preferablyless than 1% of any other crystal form, or amorphous form, of thecompound present.

When used in reference to a diffractogram, a spectrum or data presentedin a graph, the term “substantially similar” means that the subjectdiffractogram, spectrum or data presented in a graph encompasses alldiffractograms, spectra or data presented in graphs that vary withinacceptable boundaries of experimentation that are known to a person ofskill in the art. Such boundaries of experimentation will vary dependingon the type of the subject diffractogram, spectrum or data presented ina graph, but will nevertheless be known to a person of skill in the art.

The term “treating” or “treat” or “treatment” as used herein is intendedthe application or administration of a compound or composition of theinvention to an animal that has a parasitic infestation for theeradication of the parasite or the reduction of the number of theparasites infesting the animal undergoing treatment. It is noted thatthe compositions of the invention may be used to prevent such aparasitic infestation.

It is further noted that in this disclosure and particularly in theclaims or paragraphs, terms such as “comprises”, “comprised”,“comprising” and the like can have the meaning attributed to it in U.S.Patent law; e.g., they can mean “includes”, “included”, “including”, andthe like; and that terms such as “consisting essentially of” and“consists essentially of” have the meaning ascribed to them in U.S.Patent law, e.g., they allow for elements not explicitly recited, butexclude elements that are found in the prior art or that affect a basicor novel characteristic of the invention.

As described herein, the compound of formula (Ia) can be a crystallineform that may exist as one or more polymorphs, including solvate forms.In general, polymorphs (alternatively known in the art as polymorphforms, polymorphic forms or crystal forms) differ with respect to theirX-ray powder diffraction patterns, spectroscopic, physicochemical andpharmacokinetic properties, as well as their thermodynamic stability.Also, polymorphs may show different physical properties like crystalshape, chemical stability, dissolution rate and bioavailability as knownfor polymorphs. Accordingly, a particular polymorph may represent themost suitable form for a given application, including, but not limitedto, use in particular administration forms such as suspensions,ointments, tablets or capsules, or in the manufacture of a drug formhaving preferred pharmacokinetic properties.

Depending upon the intended use of the solid state form of(S)-afoxolaner, processing considerations may favor selection of aspecific solid state form or a specific combination of such solid stateforms. Use of a solvated crystalline form, instead of Form I or Form IIin a composition, eliminates a processing step, namely desolvation, forthose processes that otherwise would proceed by desolvation of asolvated crystalline form. However, in the pharmaceutical or veterinaryfields, certain solvents are not permitted above threshold levels due totoxicity concerns and must be removed in order to be used in productsthat are administered to humans or animals. Accordingly, the use ofcertain solvates is not possible in these fields. Furthermore, it isdifficult to remove solvents from crystalline forms of a compound wherethe solvent is part of the crystal lattice. When a non-solvatedcrystalline solid form of a compound can be produced the desolvationstep can be eliminated, resulting in an improved manufacturing processof the compound. For example, if Form I or Form II is directlycrystallized from an appropriate solvent without intervening preparationand desolvation of an intermediate solvated crystalline form significantcost savings and more efficient process is achieved. See, for example,E. Shefter and T. Higuchi, have measured the relative rates ofdissolution of several crystalline solvated and non-solvated forms ofimportant pharmaceuticals. J. Pharm. Sci., 52 (8). (1963), 781-91. Inthe case of the compound of formula (Ia) shown below, it was found thatcrystallization of the compound from common process solvents, includingaromatic solvents such as toluene and the like, resulted in isolation ofthe compound as a solvate and isolation of a non-solvated form of thecompound of formula (Ia) was very difficult. However, the solvate couldnot be directly used in pharmaceutical or veterinary applicationswithout significantly reducing the level of the solvent, which was notcommercially feasible. Therefore, the discovery of the non-solvated FormI and Form II of the compound of formula (Ia) represents a significantimprovement in the development of effective parasiticidal compositionsfor treating or preventing parasitic infestations in animals.

In another embodiment of the invention, solvates, including hydrates,have some variability in the exact molar ratio of their componentsdepending on a variety of conditions understood to a person of skill inthe art. For example, a molar ratio of components within a solvateprovides a person of skill in the art information as to the generalrelative quantities of the components of the solvate and in many casesthe molar ratio may vary by about plus or minus 20% from a stated range.For example, a molar ratio of 1:1 is understood to include the ratio1:0.8 as well as 1:1.2 as well as all of the individual ratios inbetween.

The present invention provides crystalline (S)-afoxolaner Form Isubstantially free of bound organic solvent, and free of bound water, ascharacterized by X-Ray Powder Diffraction (XRPD) and/or DifferentialScanning Calorimetry (DSC) described in Example 3.

The present invention also provides crystalline (S)-afoxolaner Form IIsubstantially free of bound organic solvent, and free of bound water, ascharacterized by X-Ray Powder Diffraction (XRPD) and/or DifferentialScanning Calorimetry (DSC) described in Example 3.

In addition, the present invention provides a process for preparing(S)-afoxolaner Form I and/or (S)-afoxolaner Form II, or a mixturethereof, comprising crystallizing the compound from a solvent mixturecomprising an aliphatic solvent and a co-solvent.

Embodiments of the present invention as described in the Summary of theInvention include those described below.

Embodiment (1)

A crystalline compound of formula (Ia), designated as Form I,

wherein said crystals are characterized by having an x-ray powderdiffraction pattern comprising three, four, five, six, seven or morepeaks selected from the group consisting of: 10.03°, 10.48°, 13.16°,15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52°, and28.13° 2θ±0.2 as determined on a diffractometer using Cu-Kα radiation.

Embodiment 2

The crystalline compound of formula (Ia) according to Embodiment (1),characterized by having an x-ray powder diffraction pattern comprisingthree or more peaks selected from the group consisting of: 10.03°,10.48°, 13.16°, 20.16°, and 22.15° 2θ±0.2 as determined on adiffractometer using Cu-Kα radiation.

Embodiment 3

The crystalline compound of formula (Ia) according to Embodiment (1),characterized by having an x-ray powder diffraction patternsubstantially similar to FIG. 1.

Embodiment 4

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (3), characterized by having a differential scanningcalorimetry (DSC) thermogram having an peak at a temperature of about146° C., and an onset at about 143° C., measured with the heating rateof 5° C./min.

Embodiment 5

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (4), characterized by having a differential scanningcalorimetry (DSC) thermogram having a heat of fusion of about 61.7 J/g.

Embodiment 6

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (5), characterized by having a differential scanningcalorimetry thermogram substantially similar to FIG. 2.

Embodiment 7

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (6), wherein the crystalline form is isolated.

Embodiment 8

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (7), wherein the crystalline form is non-solvated.

Embodiment 9

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (8), which is enantiomerically pure.

Embodiment 10

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (9), having a degree of chemical purity of at leastabout 95%.

Embodiment 11

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (10), having a degree of chemical purity of at leastabout 98%.

Embodiment 12

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (10), having a degree of chemical purity of at leastabout 99%.

Embodiment 13

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (12), having a degree of chemical purity in the rangeof about 98.00% to about 99.00%.

Embodiment 14

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (13), having a degree of chemical purity in the rangeof about 99.00% to about 99.95%.

Embodiment 15

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (13), having a degree of chemical purity in the rangeof about 99.00% to about 100%.

Embodiment 16

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (15), having a degree of chemical purity of about99.90%.

Embodiment 17

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (16), having an enantiomeric purity in the range ofabout 98.0 to about 99.0%.

Embodiment 18

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (17), having an enantiomeric purity in the range ofabout 99.0 to about 100%.

Embodiment 19

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (18), having a degree of chemical purity in the rangeof about 99.00% to about 99.95% and an enantiomeric purity in the rangeof about 99.0 to about 100%.

Embodiment 20

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (19), having a degree of chemical purity of about99.90% and an enantiomeric purity of about 99.90%.

Embodiment 21

The crystalline compound of formula (Ia) according to any one ofEmbodiments (1) to (20), in substantially pure crystal form.

Embodiment 22

A crystal form of (S)-afoxolaner which is bioequivalent to thecrystalline compound of formula (Ia) according to any one of Embodiments(1) to (21).

Embodiment 23

A pharmaceutical composition comprising the crystalline compound offormula (Ia) according to any one of Embodiments (1) to (22), and atleast one pharmaceutically acceptable excipient.

Embodiment 24

A composition comprising the crystalline compound of formula (Ia)according to any one of Embodiments (1) to (22), wherein saidcrystalline compound of formula (Ia) is in admixture with one or moredistinct polymorphic forms of, or an amorphous compound of, formula(Ia).

Embodiment 25

The composition according to Embodiment (24), wherein said distinctpolymorphic form is Form II.

Embodiment 26

The composition according to Embodiment (24), wherein said crystallinecompound of formula (Ia) is in admixture with an amorphous compound offormula (Ia).

Embodiment 27

The pharmaceutical composition according to any one of Embodiments (23)to (26), wherein the composition comprises at least about 50.0% byweight of the crystalline compound of formula (Ia) according toembodiment 1, based on the total weight of compound of formula (Ia) inthe composition.

Embodiment 28

The pharmaceutical composition according to any one of Embodiments (23)to (27), wherein the composition comprises at least about 70% by weightof the crystalline compound of formula (Ia) according to embodiment 1,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 29

The pharmaceutical composition according to any one of Embodiments (23)to (28), wherein the composition comprises at least about 80% by weightof the crystalline compound of formula (Ia) according to embodiment 1,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 30

The pharmaceutical composition according to any one of Embodiments (23)to (29), wherein the composition comprises at least about 90% by weightof the crystalline compound of formula (Ia) according to embodiment 1,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 31

The pharmaceutical composition according to any one of Embodiments (23)to (28), wherein the composition comprises at least about 95% by weightof the crystalline compound of formula (Ia) according to embodiment 1,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 32

The pharmaceutical composition according to any one of Embodiments (23)to (31), wherein the composition comprises at least about 99.0% byweight of crystalline compound of formula (Ia) according to embodiment1, based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 33

A process for preparing a crystalline compound of formula (Ia) accordingto any one of Embodiments (1) to (22), which comprises:—

(a) heating a mixture of a toluene solvate of (S)-afoxolaner in asolvent, wherein the solvent is acetonitrile, ethyl acetate, a linear,branched or cyclic aliphatic solvent (e.g. pentane, hexane, heptane,octane, cyclopentane, cyclohexane and the like) or an alcohol, or acombination thereof, until dissolution has occurred;(b) optionally adding a co-solvent;(c) reducing the temperature of the solvent system to induce nucleation;(d) maintaining the mixture at a temperature below that at whichnucleation has commenced; and(e) isolating the crystalline compound of formula (Ia) so deposited.

Embodiment 34

The process according to Embodiment (33), wherein the co-solvent isisobutyl ketone or acetone.

Embodiment 35

The process according to Embodiment (33), wherein the aliphatic solventis a C₁-C₈ linear, branched or cyclic alkane solvent

Embodiment 36

The process according to according to any one of Embodiments (33) to(35), wherein the alcohol is a lower alkyl alcohol.

Embodiment 37

The process according to according to any one of Embodiments (33) to(36), wherein the alcohol is ethanol.

Embodiment 38

The process according to any one of Embodiments (33) to (37), whereinthe solvent is a mixture comprising ethanol and cyclohexane.

Embodiment 39

The process according to Embodiment (38), wherein the mixture of ethanoland cyclohexane is about 10:90 to about 99:1 (v/v) ethanol tocyclohexane.

Embodiment 40

The process according to Embodiment (38), wherein the mixture of ethanoland cyclohexane is about 1:99 to about 25:75 (v/v) ethanol tocyclohexane.

Embodiment 41

The process according to Embodiment (38), wherein the mixture of ethanoland cyclohexane is about 3:97 to about 10:90 (v/v) ethanol tocyclohexane.

Embodiment 42

The process of according to Embodiment (38) wherein the mixture ofethanol and cyclohexane is about 5:95 to about 10:90 (v/v) ethanol tocyclohexane.

Embodiment 43

The process of according to Embodiment (38) wherein the mixture ofethanol and cyclohexane is about 8:92 (v/v) ethanol to cyclohexane.

Embodiment 44

The process according to any one of Embodiments (33) to (43), comprisingseeding with enantiomerically pure (S)-afoxolaner Form I.

Embodiment 45

The process according to any one of Embodiments (33) to (44), whereinthe heating is to about 50 to about 80 degrees Celsius.

Embodiment 46

The process according to any one of Embodiments (33) to (45), whereinreducing the temperature is to a temperature of about 10 degrees Celsiusor lower.

Embodiment 47

The process according to any one of Embodiments (33) to (46), whereinreducing the temperature is to a temperature of about 5 degree Celsiusor lower.

Embodiment 48

The process according to any one of Embodiments (33) to (47), whereinreducing the temperature is at a rate of about 3 degrees Celsius/hour.

Embodiment 49

A process for preparing a crystalline Form I of (S)-afoxolaner ofembodiment 1 which comprises:—

(a) heating a mixture of the toluene solvate of (S)-afoxolaner having anenantiomeric purity ≥97% in a solvent, wherein the solvent isacetonitrile, ethyl acetate, a linear, branched or cyclic alkane solventor an alcohol, or a combination thereof, until dissolution has occurred;(b) optionally adding a co-solvent;(c) reducing the temperature of the solvent system to induce nucleation;(d) maintaining the mixture at a temperature below that at whichnucleation has commenced; and(e) isolating the crystalline Form I of (S)-afoxolaner so deposited.

Embodiment 50

A process according to according to any one of Embodiments (33) to (49),in which the crystalline compound of formula (Ia) isolated isenantiomerically enriched with (S)-afoxolaner.

Embodiment 51

A crystalline form of (S)-afoxolaner produced by the process accordingto any one of Embodiments (33) to (50).

Embodiment 52

A crystalline form of (S)-afoxolaner as disclosed in any of theexamples.

Embodiment 53

A method of treating or preventing parasitic infection or infestation inan animal comprising administering to the animal an effective amount ofa crystalline form of (S)-afoxolaner of any one of Embodiments (1) to(22) or Embodiment (52) or a composition of any one of Embodiments23-32.

Embodiment 54

A crystalline compound of formula (Ia), designated as Form II,

wherein said crystals are characterized by having an x-ray powderdiffraction pattern comprising three, four, five, six, seven or morepeaks selected from the group consisting of: 5.99°, 12.99°, 15.80°,18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11° and 29.00° 2θ±0.2 asdetermined on a diffractometer using Cu-Kα radiation.

Embodiment 55

The crystalline compound of formula (Ia) according Embodiment (54),wherein said crystals are characterized by having an x-ray powderdiffraction pattern comprising three or more peaks selected from thegroup consisting of: 5.99°, 12.99°, 15.80°, 22.17°, 26.110 2θ±0.2 asdetermined on a diffractometer using Cu-Kα radiation.

Embodiment 56

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) or (55), characterized by having an x-ray powderdiffraction pattern substantially similar to FIG. 3.

Embodiment 57

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (56), characterized by having a differentialscanning calorimetry (DSC) thermogram having an peak at a temperature ofabout 149° C., and an onset at about 146° C., measured with the heatingrate of 5° C./min.

Embodiment 58

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (57), characterized by having a differentialscanning calorimetry (DSC) thermogram having a heat of fusion about 65.7J/g.

Embodiment 59

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (58), characterized by having a differentialscanning calorimetry thermogram substantially similar to FIG. 4.

Embodiment 60

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (59), wherein the crystalline form is isolated.

Embodiment 61

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (60), wherein the crystalline form is non-solvated.

Embodiment 62

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (61), which is enantiomerically pure.

Embodiment 63

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (62), having a degree of chemical purity of at leastabout 95%.

Embodiment 64

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (63), having a degree of chemical purity of at leastabout 98%.

Embodiment 65

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (64), having a degree of chemical purity of at leastabout 99%.

Embodiment 66

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (65), having a degree of chemical purity in therange of about 98.00% to about 99.00%.

Embodiment 67

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (66), having a degree of chemical purity in therange of about 99.00% to about 99.95%.

Embodiment 68

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (67), having a degree of chemical purity in therange of about 99.00% to about 100%.

Embodiment 69

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (68), having a degree of chemical purity of about99.90%.

Embodiment 70

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (69), having an enantiomeric purity in the range ofabout 98.0 to about 99.0%.

Embodiment 71

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (70), having an enantiomeric purity in the range ofabout 99.0 to about 100%.

Embodiment 72

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (70), having a degree of chemical purity in therange of about 99.00% to about 99.95% and an enantiomeric purity in therange of about 99.0 to about 100%.

Embodiment 73

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (72), having a degree of chemical purity of about99.90% and an optical purity of about 99.90%.

Embodiment 74

The crystalline compound of formula (Ia) according to any one ofEmbodiments (54) to (73), in substantially pure crystal form.

Embodiment 75

A crystal form of (S)-afoxolaner which is bioequivalent to thecrystalline compound of formula (Ia) according to any one of Embodiments(54) to (74).

Embodiment 76

A pharmaceutical composition comprising the crystalline compound offormula (Ia) according to any one of Embodiments (54) to (75), and atleast one pharmaceutically acceptable excipient.

Embodiment 77

A composition comprising the crystalline compound of formula (Ia)according to Embodiment (76), wherein said crystalline compound offormula (Ia) is in admixture with one or more distinct polymorphic formsof, or an amorphous compound of, formula (Ia).

Embodiment 78

The composition according to Embodiment (77), wherein said distinctpolymorphic form is Form I.

Embodiment 79

The composition according to Embodiment (77), wherein said crystallinecompound of formula (Ia) is in admixture with an amorphous compound offormula (Ia).

Embodiment 80

The pharmaceutical composition according to any one of Embodiments (76)to (79), wherein the composition comprises at least 50.0% by weight ofthe crystalline compound of formula (Ia) according to embodiment 53,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 81

The pharmaceutical composition according to any one of Embodiments (76)to (80), wherein the composition comprises at least about 70% by weightof the crystalline compound of formula (Ia) according to embodiment 53,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 82

The pharmaceutical composition according to any one of Embodiments (76)to (81), wherein the composition comprises at least about 80% by weightof the crystalline compound of formula (Ia) according to embodiment 53,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 83

The pharmaceutical composition according to any one of Embodiments (76)to (80), wherein the composition comprises at least about 90% by weightof the crystalline compound of formula (Ia) according to embodiment 53,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 84

The pharmaceutical composition according to any one of Embodiments (76)to (83), wherein the composition comprises at least about 95% by weightof the crystalline compound of formula (Ia) according to embodiment 53,based on the total weight of compound of formula (Ia) in thecomposition.

Embodiment 85

The pharmaceutical composition according to any one of Embodiments (76)to (84), wherein the composition comprises at least 99.0% by weight ofcrystalline compound of formula (Ia) according to embodiment 53, basedon the total weight of compound of formula (Ia) in the composition.

Embodiment 86

A process for preparing a crystalline compound of formula (Ia) accordingto Embodiment (54), which comprises:—

(a) heating a mixture of the toluene solvate of (S)-afoxolaner in asolvent, wherein the solvent is acetonitrile, ethyl acetate, a linear,branched or cyclic aliphatic solvent (e.g. pentane, hexane, heptane,octane, cyclopentane, cyclohexane and the like) or an alcohol, or amixture thereof, until dissolution has occurred;(b) optionally adding a co-solvent;(c) reducing the temperature of the solvent system to induce nucleation;(d) maintaining the mixture at a temperature below that at whichnucleation has commenced; and(e) isolating the crystalline compound of formula (Ia) so deposited.

Embodiment 87

The process according to Embodiment (86), wherein the co-solvent isisobutyl ketone or acetone.

Embodiment 88

The process according to any one of Embodiments (86) to (87), whereinthe alcohol is ethanol.

Embodiment 89

The process according to any one of Embodiments (86) to (88), whereinthe solvent is a mixture comprising ethanol and cyclohexane.

Embodiment 90

The process of embodiment 89 wherein the mixture of ethanol andcyclohexane is about 15:85 to about 99:1 (v/v) ethanol to cyclohexane.

Embodiment 91

The process according to Embodiment (89), wherein the mixture of ethanoland cyclohexane is about 1:99 to about 25:75 (v/v) ethanol tocyclohexane.

Embodiment 92

The process according to Embodiment (89), wherein the mixture of ethanoland cyclohexane is about 3:97 to about 10:90 (v/v) ethanol tocyclohexane.

Embodiment 93

The process of according to Embodiment (89) wherein the mixture ofethanol and cyclohexane is about 5:95 to about 10:90 (v/v) ethanol tocyclohexane.

Embodiment 94

The process according to any one of Embodiments (89) to (91), whereinthe mixture of ethanol and cyclohexane is about 15:85 (v/v) ethanol tocyclohexane.

Embodiment 95

The process according to any one of Embodiments (86) to (94), comprisingseeding with enantiomerically pure (S)-afoxolaner Form II.

Embodiment 96

The process according to any one of Embodiments (86) to (95), whereinthe heating is to about 50 to about 80 degrees Celsius.

Embodiment 97

The process according to any one of Embodiments (86) to (96), whereinreducing the temperature is to a temperature of about 10 degrees Celsiusor lower.

Embodiment 98

The process according to any one of Embodiments (86) to (97), whereinreducing the temperature is to a temperature of about 5 degree Celsiusor below.

Embodiment (99)

The process according to any one of Embodiments (86) to (98), whereinreducing the temperature is at a rate of about 3 degrees Celsius/hour.

Embodiment 100

A process for preparing a crystalline Form II of (S)-afoxolaneraccording to Embodiment (54), which comprises:—

(a) heating a mixture of the toluene solvate of (S)-afoxolaner having anenantiomeric purity of about 97% to about 100% in a solvent, wherein thesolvent is acetonitrile, ethyl acetate, a linear, branched or cyclicalkane or an alcohol, or a mixture thereof, until dissolution hasoccurred;(b) optionally adding a co-solvent;(c) reducing the temperature of the solvent system to induce nucleation;(d) maintaining the mixture at a temperature below that at whichnucleation has commenced; and(e) isolating the crystalline Form II of (S)-afoxolaner so deposited.

Embodiment 101

A crystalline form of (S)-afoxolaner produced by the process accordingto any one of Embodiments (86) to (100).

Embodiment 102

A method of treating or preventing parasitic infection or infestation inan animal comprising administering to the animal an effective amount ofa crystalline form of formula (Ia) according to any one of Embodiments(54) to (75) or a composition according to Embodiments 76 to 85.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form I that exhibits one or more of the characteristicpeaks expressed in degrees 2-theta (2θ)±0.2 shown in Table 1 below.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form I that exhibits at least seven of the characteristicpeaks expressed in degrees 2-theta (2θ)±0.2 at one or more of thepositions shown in Table 1 below.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form I that exhibits an endotherm as described in theExamples and shown in FIG. 2.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form I in combination with crystalline (S)-afoxolanerForm II and/or amorphous (S)-afoxolaner. In another embodiment, theinvention provides pesticidal or parasiticidal compositions comprising acrystalline (S)-afoxolaner Form I alone, or in combination with one ormore additional active agents, and agriculturally or pharmaceuticallyacceptable carriers or diluents, wherein at least 80% of the solid formof (S)-afoxolaner is a crystalline Form I.

In one embodiment, the invention provides a crystalline (S)-afoxolanerForm II that exhibits one or more of the characteristic peaks expressedin degrees 2-theta (2θ)±0.2 shown in Table 1 below.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form II that exhibits at least seven of thecharacteristic peaks expressed in degrees 2-theta (2θ)+0.2 at one ormore of the positions shown in Table 1 below.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form II that exhibits an endotherm as described in theExamples and shown in FIG. 4.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form II in combination with crystalline (S)-afoxolanerForm I and/or amorphous (S)-afoxolaner. In another embodiment, theinvention provides pesticidal or parasiticidal compositions comprising acrystalline (S)-afoxolaner Form II alone, or in combination with one ormore additional active agents, and agriculturally or pharmaceuticallyacceptable carriers or diluents, wherein at least 80% of the solid formof (S)-afoxolaner is a crystalline Form II.

In other embodiments, the polymorph may contain impurities. Non-limitingexamples of impurities residual organic and inorganic molecules such assolvents, water or salts. In one embodiment, the polymorph contains lessthan 10% by weight total impurities.

In another embodiment, the polymorph contains less than 5%, less than4%, less than 3%, less than 2%, by weight total impurities. In anotherembodiment, the polymorph contains less than 1% by weight totalimpurities. In still another embodiment, the polymorph is substantiallyfree from impurities.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form I, wherein at least 90% of the solid form is acrystalline Form I form.

In another embodiment, the invention provides a crystalline(S)-afoxolaner, wherein at least 80% of the solid form is a crystallinetoluene solvate form.

In another embodiment, the invention provides a crystalline(S)-afoxolaner Form II, wherein at least 90% of the solid form is acrystalline Form II form.

In a particular embodiment, polymorph Form I is in a substantially purecrystal form. In another embodiment, polymorph Form I has less than 10%of other crystal forms. Preferably, there is less than 5%, morepreferably less than 2%, and even more preferably less than 1% of anyother crystal form, or amorphous form, of the compound present.

Similarly, in a particular embodiment, polymorph Form II is in asubstantially pure crystal form. In another embodiment, polymorph FormII has less than 10% of other crystal forms. Preferably, there is lessthan 5%, more preferably less than 2%, and even more preferably lessthan 1% of any other crystal form, or amorphous form, of the compoundpresent.

In one embodiment, crystalline Form I and/or Form II of (S)-afoxolanermay be prepared by crystallizing (S)-afoxolaner from a combination of alower alcohol solvent and an aliphatic solvent according to knownmethods in the art. In another embodiment, Form I and/or Form II of(S)-afoxolaner may be prepared by crystallizing the compound from analkyl ester solvent or a solvent mixture containing an alkyl estersolvent. Alkyl ester solvents include, but not limited to, an alkylacetate solvent such as ethyl acetate, isopropyl acetate, methylacetate, and the like. In yet another embodiment, Form I and/or Form IIof (S)-afoxolaner may be prepared by crystallizing the compound from anitrile solvent or a solvent mixture containing a nitrile solvent.Nitrile solvents include, but are not limited to acetonitrile. Inanother embodiment, Form I and/or Form II of (S)-afoxolaner may beprepared by crystallizing the compound from a combination of analiphatic solvent and an alkylester solvent. In yet another embodiment,Form I and/or Form II (S)-afoxolaner may be prepared by crystallizingthe compound from a nitrile solvent including acetonitrile.

In another embodiment, the crystalline (S)-afoxolaner Form I and/or(S)-afoxolaner Form II may be crystallized from water, ethanol,isopropanol, methanol, toluene, dichloromethane, hexane, cyclohexane,diisopropylether or chlorobutane, or a mixture thereof.

Aliphatic solvents are straight, branched, cyclic, primary, secondary ortertiary hydrocarbons and include, but are not limited to, pentane,hexanes, heptane, octane, cyclopentane, cyclohexane, and the like. Inanother embodiment, crystalline (S)-afoxolaner Form I and/or Form II maybe prepared by crystallizing (S)-afoxolaner from a solvent combinationof a lower alcohol solvent and a cycloalkyl solvent. In anotherembodiment, crystalline (S)-afoxolaner Form I and/or Form II may beprepared by crystallizing (S)-afoxolaner from a solvent combination ofan alkylester solvent and an aliphatic solvent. In yet anotherembodiment, crystalline (S)-afoxolaner Form I and/or Form II may beprepared by crystallizing (S)-afoxolaner from a solvent combination of anitrile solvent and an aliphatic solvent.

In one embodiment of the process, the ratio of the lower alcohol solventto the aliphatic solvent is about between 1:99 (v/v) to about 25:75(v/v), lower alcohol to aliphatic solvent. In another embodiment, theratio of lower alcohol solvent to aliphatic solvent is about 2:98 (v/v)to about 20:80 (v/v). In still another embodiment, the ratio of loweralcohol solvent to aliphatic solvent is about 4:96 to about 15:85. Inanother embodiment, the ratio of lower alcohol solvent to aliphaticsolvent is about 5:95 to about 10:90. In one embodiment, the ratio oflower alcohol solvent to aliphatic solvent is about 6:94 (v/v). Inanother embodiment, the ratio of lower alcohol solvent to aliphaticsolvent is about 7:93 (v/v). In another embodiment, the ratio of loweralcohol solvent to aliphatic solvent is about 8:92 (v/v).

The total volume of solvent may be varied in the process. However, usingtoo much solvent may impact the yield of the process. In contrast, usingtoo little solvent may result in a lower quality product asco-crystallization of an alternate solid form or impurities is morelikely. In one embodiment about 7 volumes to about 30 volumes of totalsolvent or a mixture of solvents may be used. In another embodiment,about 10 volumes to about 25 volumes of total solvent or solvent mixturemay be used in the crystallization. In another embodiment about 12volumes to about 20 volumes of solvent or solvent mixture may be used.In other embodiments, about 12 volumes to 18 volumes, about 13 volumesto about 17 volumes or about 14 volumes to about 16 volumes may be used.In one embodiment, about 15 volumes of total solvent or solvent mixturemay be used to crystallize Form I or Form II (S)-afoxolaner.

The source of (S)-afoxolaner may be amorphous (S)-afoxolaner or othersolid forms of the compound. Alternatively, a solution of (S)-afoxolanerin another solvent may be used. In one embodiment, the enantiomericpurity of (S)-afoxolaner used in the process is at least about 90% (e.g.ratio of 90:10, (S)-enantiomer to (R)-enantiomer). In anotherembodiment, the enantiomeric purity of the (S)-afoxolaner is at leastabout 95%. Preferably, the enantiomeric purity of (S)-afoxolaner used inthe process is at least about 98%. In one embodiment, (S)-afoxolaner isdissolved in a suitable solvent at a concentration in which the mixtureis a suspension at ambient temperature or below and a solution atelevated temperature and then cooled slowly to induce crystallizationfrom the solvent. In another embodiment, (S)-afoxolaner is dissolved ina solvent in which it is reasonably soluble and then a second solvent inwhich the compound is not very soluble is added slowly to inducecrystallization.

Optionally, a seed can be added to aid crystallization. The seed shouldbe enriched in the desired enantiomer to direct the crystallization tothat enantiomer. The enantiomeric excess of the seed can be the same asor different to that of the afoxolaner solution to which it is added,but preferably it is of high enantiomeric excess, eg, at least 90% ee,or higher. Similarly, the seed can be the desired racemic compound todirect the crystallization to that racemic compound.

In an embodiment of the invention, seed crystals may be added to inducecrystallization of the (S)-afoxolaner. The amount of seed crystals of(S)-afoxolaner added is such that it exceeds the saturation amount inthe solvent being used so that there are undissolved seed crystalspresent in the solution. A person of skill in the art will understandthat the seeding temperature will depend on the solvent used, and if asolvent mixture is used, on the ratio of solvents. In one embodiment,wherein a solvent mixture comprising an aliphatic solvent and a loweralcohol solvent is used, seeding may be done at a temperature range ofabout 50° C. to about 60° C. In another embodiment, seeding may beconducted at a temperature of about 52° C. to about 58° C. In yetanother embodiment, seeding may be done at a temperature of about 53° C.to 57° C. In yet another embodiment, seeding may be done at 55° C.

The mixture is allowed to stand at a temperature of from about 10*C toabout 65° C., preferably about 10° C. to about 60° C. or about 10° C. toabout 30° C. In one embodiment, the mixture after seeding is aged at atemperature of about 25° C. to about 45° C. and aged and then heated toa temperature of about 50° C. to about 60° C. and aged again beforecooling further to isolate the crystallized product. This this cycle maybe repeated. The heating/cooling cycle may be used to increase the sizeof the crystals formed; however, this process is not absolutelynecessary. In one embodiment, the mixture is allowed to age at thedesired temperature for at least about 15 minutes. In other embodiments,the mixture is allowed to age at least about 30 minutes or at leastabout 1 hour. In other embodiments, the mixture is allowed to age at thedesired temperature at least about 2 hours, at least about 3 hours, orlonger. The length of the age time may affect the yield of the processif the aging time is not sufficient to achieve equilibrium solubility atthe aging temperature; however, as long as the mixture is stable thelength of the aging step is not critical and the mixture may be kept fora longer period of time at the aging temperature. In one embodiment, themixture is aged at the desired temperature from about 2 hours to about27 hours. The crystallized mixture is then cooled further to atemperature of below about 20° C. and aged prior to isolation of thecrystals by filtration or centrifugation. In one embodiment, the mixtureis cooled to a temperature of about 0° C. to about 20° C. In anotherembodiment, the mixture is cooled to a temperature of about 0° C. toabout 15° C. or about 5° C. to about 20° C. In yet another embodiment,the mixture is cooled to a temperature of about 5° C. to about 15° C. orabout 5° C. to about 10° C. and aged a sufficient amount of time beforeisolation of the crystals.

The cooled mixture is aged for a sufficient amount of time beforeisolation. The length of aging before isolation may be varied without asignificant impact on the yield. In one embodiment, the mixture iscooled at least about 15 minutes. In another embodiment, the mixture isaged for at least about 30 minutes or at least about 1 hour beforeisolation. In another embodiment, the mixture is aged for at least about2 hours, at least about 3 hours, at least about 4 hours, at least about5 hours, or longer. In other embodiments, the mixture may be aged atleast about 10 hours, at least about 15 hours, at least about 20 hoursor at least about 24 hours, or longer.

In another embodiment of the invention, the crystals may be collected byfiltration or centrifugation and optionally washed to remove residualethanol. Drying, if desired may also be carried out. Appropriate dryingconditions should be chosen to avoid melting of compound of formula(Ia). For example, extreme heat should be avoided during dryingconditions.

The invention further relates to enantiomerically pure (S)-afoxolanerbeing in a crystalline form. The crystalline form may be more stable,easier to handle and store, and easier to purify and easier tosynthesize in a reproducible manner.

In one aspect, pharmaceutical compositions are provided comprisingcompound of formula (Ia), for example polymorph Form I, or polymorphForm II, or a mixture thereof, and a pharmaceutically acceptable carrieror diluent. For example, in one embodiment a pharmaceutical compositionis provided comprising polymorph Form I, and a pharmaceuticallyacceptable carrier or diluent. In another embodiment, the inventionprovides a pharmaceutical composition comprising polymorph Form II and apharmaceutically acceptable carrier or diluent. In yet anotherembodiment, the invention provides a pharmaceutical compositioncomprising a mixture of polymorph Form I and polymorph Form II and apharmaceutically acceptable carrier or diluent.

When the compounds of the present invention are administered aspharmaceuticals to animals, e.g., mammals, they can be given per se oras a pharmaceutical composition containing, for example, 0.1% to 99.9%(w/w) (more preferably, 0.5 to 90%) of active ingredient in combinationwith a pharmaceutically acceptable carrier. In other embodiments, thepharmaceutical compositions comprises about 0.5% to about 50% (w/w),about 0.5% to about 25% (w/w) of the compound of formula (Ia) as Form I,Form II or a mixture thereof. In other embodiments, the pharmaceuticalcompositions comprise about 0.5% to about 15% (w/w) or about 0.5% toabout 10% (w/w) as Form I, Form II or a mixture thereof. In yet anotherembodiment, the pharmaceutical compositions comprise about 0.1% to about5% (w/w) or about 0.1% to about 2.5% (w/w) of the compound of formula(Ia) as Form I, Form II or a mixture thereof.

In another aspect of the invention is compositions comprising mixturesof two or more forms or mixtures of crystalline (e.g. Form I and FormII) and non-crystalline compound of formula (Ia) that may possessparticular advantages in extended release formulations. Thus, theinvention also relates to mixtures of such crystalline compound offormula (Ia) products.

In another aspect of the invention, the crystalline compound of formula(Ia) comprises a mixture of crystalline (e.g. Form I and Form II) andnon-crystalline forms. For example, the % crystallinity of the compoundof formula (Ia) can be at least about 10%, preferably at least about 20%(by weight) of the total compound of formula (Ia), preferably in anamount of at least about 30%, at least about 40%, at least about 50%, atleast about 60% (by weight) of the total compound of formula (Ia).

In one embodiment the % crystallinity of compound of formula (Ia) ispresent in a composition in an amount between about 10% and 70%,preferably between about 30% and 50% (by weight), of the total compoundof formula (Ia).

The crystal forms described herein can be combined with apharmaceutically acceptable carrier according to conventionalpharmaceutical compounding techniques. Furthermore, the carrier may takea wide variety of forms depending on the form of the preparation desiredfor administration, e.g. oral (e.g. tablets, capsules or soft chews) orparenteral (including intravenous injections or infusions). In preparingcompositions for oral dosage form any of the usual pharmaceutical mediamay be employed. Usual pharmaceutical media include, for example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents, surfactants, solvents, binders, humectants, and the like in thecase of oral liquid preparations (such as for example, suspensions,solutions, emulsions and elixirs); aerosols; or carriers such asstarches (e.g. corn starch), sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders (e.g. povidone, solidpolyethylene glycol, and the like), disintegrating agents and the like,in the case of oral solid preparations (such as for example, powders,capsules, tablets and soft chews).

Wetting agents, emulsifiers, surfactants and lubricants, such as sodiumlauryl sulfate, and magnesium stearate, as well as coloring agents,release agents, coating agents, sweetening, flavoring and perfumingagents, preservatives and antioxidants also can be present in thecompositions. Examples of pharmaceutically acceptable antioxidantsinclude: water soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, tocopherols, and the like; and metal chelatingagents, such as citric acid, ethylenediamine tetraacetic acid (EDTA),sorbitol, tartaric acid, phosphoric acid, and the like.

Examples of suitable surfactants for pharmaceutical compositions forinclude glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters,sorbitan esters including sorbitan monooleate (Span® 20), polyvinylalcohol, polysorbates including polysorbate 20 and polysorbate 80,d-ca-tocopherol polyethylene glycol 1000 succinate (TPGS), sodium laurylsulfate, co-polymers of ethylene oxide and propylene oxide (e.g.poloxamers such as LUTROL® F87 and the like), polyethylene glycol castoroil derivatives including polyoxyl 35 castor oil (Cremophor® EL),polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate(LAUROGLYCOL®); glyceride esters including glycerol caprylate/caprate(CAPMUL® MCM), polyglycolized glycerides (GELUCIRE®), PEG 300caprylic/capric glycerides (Soffigen® 767), PEG 400 caprylic/capricglycerides (Labrasol®), PEG 300 oleic glycerides (Labrafil® M-1944CS),PEG 300 linoleic glycerides (Labrafil® M-2125CS); polyethylene glycolstearates and polyethylene glycol hydroxy stearates including polyoxyl 8stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750monostearate, and the like. Surfactants may be present in thecomposition at concentrations of about 0.1% to about 10% (w/w), about 1%to about 10% (w/w) or about 5% to about 10% (w/w). More typically,surfactants may be present at concentrations of about 0.1% to about 5%(w/w) or about 1 to about 5% (w/w).

Fillers that may be used in oral formulations include, but are notlimited to, corn starch, pre-gelatinized corn starch, soy protein fines,corn cob, and corn gluten meal, and the like, or a combination thereof.Fillers are typically present in the compositions at a concentration ofabout 5% to about 80% (w/w), about 10% to about 70% (w/w), about 10% toabout 60%, about 100% to about 50% (w/w), or about 10% to about 40%(w/w). More typically, the fillers may be present at concentrations ofabout 30% to about 70%, about 30% to about 60%, about 30% to about 50%or about 35% to about 55%.

Binders that may be used in compositions of the invention for oraladministration include, but are not limited to, polyvinylpyrrolidone(e.g. Povidone), cross-linked polyvinylpyrrolidone (Crospovidone),polyethylene glycols of various grades including PEG 3350, PEG 4000, PEG6000, PEG 8000 and even PEG 20,000, and the like; co-polymers ofvinylpyrrolidone and vinyl acetate (e.g. Copovidone) such as the productsold by BASF by the tradename Kollidon® VA 64 and the like; starch suchas potato starch, tapioca starch or corn starch; molasses, corn syrup,honey, maple syrup and sugars of various types; or a combination of twoor more binders. In one embodiment, the composition comprises thebinders Povidone K30 LP and PEG 3350 or PEG 4000, or a combinationthereof. Binders are typically present in the compositions at aconcentration of about 1% to about 30% (w/w). More typically, thecompositions will include binders at a concentration of about 1% toabout 20% (w/w), about 1 to about 15% (w/w), about 1% to about 10%(w/w), about 5% to about 15% (w/w) or about 5% to about 10% (w/w).

Solvents that may be used in the compositions of the invention include,but are not limited to, various grades of liquid polyethylene glycol(PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylenecarbonate; propylene glycol; triglycerides including, but not limited tocaprylic/capric triglyceride, caprylic/capric/linoleic triglyceride(e.g. MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride,propylene glycol dicaprylate/dicaprate, and the like; water, sorbitolsolution, glycerol caprylate/caprate and polyglycolized glycerides(GELUCIRE®), 2-pyrrolidone, N-methylpyrrolidone (NMP),dimethylacetamide, or a combination thereof.

Solvents may be included in the compositions in concentrations of about1 to about 50% (w/w). In other embodiments, the concentration of thesolvents will be from about 1 to about 40% (w/w), about 1 to about 30%(w/w) or about 1 to about 20% (w/w). More typically, the solvents willbe in the compositions at concentrations of about 5% to about 20% (w/w)or about 5% to about 15% (w/w).

Humectants that may be used in the compositions include, but are notlimited to, glycerol (also referred to herein as glycerin), propyleneglycol, cetyl alcohol and glycerol monostearate, and the like.Polyethylene glycols of various grades may also be used as humectants.Humectants may typically present in the compositions at a concentrationof about 1% to about 25% (w/w). Typically, the concentration of thehumectant in the composition of the invention will be 1% to about 20%(w/w), about 1% to about 15% (w/w) or about 5% to about 15% (w/w). Moretypically, the compositions of the invention will contain about 1% toabout 10% (w/w) humectant.

Pharmaceutical compositions comprising a crystal form of the compound offormula (Ia) (e.g. Form I and/or Form II) may be formulated to have anyconcentration desired, preferably an amount which is therapeuticallyeffective and would not cause one or more unwanted side effects.

Because of their ease of administration, tablets, soft chew dosage formsand capsules may represent the most advantageous oral dosage unit form,in which case solid pharmaceutical carriers may be employed. If desired,tablets and soft chew dosage forms may be coated by techniques known tothose in the art.

In certain embodiments, the pharmaceutical composition comprises varyingamounts of a crystal form of the compound of formula (Ia), based on thetotal weight of compound of formula (Ia) in the composition. In oneembodiment, the pharmaceutical composition comprises less than 1% byweight of the crystal form of the polymorph Form I of compound offormula (Ia). In another embodiment, the pharmaceutical compositioncomprises less than 1% by weight of the crystal form of the polymorphForm I of compound of formula (Ia). In another embodiment, thepharmaceutical composition comprises less than 10% by weight of thecrystal form of the polymorph Form I of compound of formula (Ia). Inanother embodiment, the pharmaceutical composition comprises less than25% by weight of the polymorph Form I of the compound of formula (Ia).

In another embodiment, the pharmaceutical composition comprises lessthan 50% by weight of the polymorph Form I of the compound of formula(Ia). In another embodiment, the pharmaceutical composition comprisesless than 99% by weight of the polymorph Form I of the compound offormula (Ia).

In other embodiments, the pharmaceutical compositions of the inventioncomprise at least about 30% (w/w), at least about 50% (w/w) or at leastabout 70% (w/w) of a compound of formula (Ia) as polymorph Form I. Inanother embodiment, the pharmaceutical compositions of the inventioncomprise at least about 80% (w/w), at least about 90% (w/w) or at leastabout 95% (w/w) of the compound of formula (Ia) as polymorph Form I. Inyet another embodiment, the compositions of the invention comprise atleast about 99% (w/w) of the compound of formula (Ia) as Form I.

In another embodiment, the pharmaceutical composition comprises lessthan 1% by weight of the crystal form of the polymorph Form II ofcompound of formula (Ia). In another embodiment, the pharmaceuticalcomposition comprises less than 1% by weight of the crystal form of thepolymorph Form II of compound of formula (Ia). In another embodiment,the pharmaceutical composition comprises less than 10% by weight of thecrystal form of the polymorph Form II of compound of formula (Ia). Inanother embodiment, the pharmaceutical composition comprises less than25% by weight of the polymorph Form II of the compound of formula (Ia).

In another embodiment, the pharmaceutical composition comprises lessthan 50% by weight of the polymorph Form II of the compound of formula(Ia). In another embodiment, the pharmaceutical composition comprisesless than 99% by weight of the polymorph Form II of the compound offormula (Ia).

In other embodiments, the pharmaceutical compositions of the inventioncomprise at least about 30% (w/w), at least about 50% (w/w) or at leastabout 70% (w/w) of a compound of formula (Ia) as polymorph Form II. Inanother embodiment, the pharmaceutical compositions of the inventioncomprise at least about 80% (w/w), at least about 90% (w/w) or at leastabout 95% (w/w) of the compound of formula (Ia) as polymorph Form II. Inyet another embodiment, the compositions of the invention comprise atleast about 99% (w/w) of the compound of formula (Ia) as Form II.

Pharmaceutical compositions include those suitable for oral, sublingual,nasal, rectal, vaginal, topical (e.g. spot-ons or pour-ons), buccal andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route will depend on thenature and severity of the condition being treated. The compositions maybe conveniently presented in unit dosage form, and prepared by any ofthe methods well known in the art of pharmacy. In certain embodiments,the pharmaceutical composition is formulated for oral administration inthe form of a pill, capsule, soft chewable dosage forms, lozenge ortablet. In other embodiments, the pharmaceutical composition is in theform of a suspension.

Pharmaceutical compositions comprising a specific crystal form can beidentified by comparison of the compositions' X-ray powder diffractionpatterns to an X-ray powder diffraction pattern of the pure specificcrystal form. It will be appreciated that pharmaceutical compositionscomprising a specific crystal form may exhibit non-identical X-raypowder diffraction patterns as compared to an X-ray powder diffractionpattern of the pure specific polymorphic crystal form.

Also provided herein are crystal forms that are bioequivalent to any oneor more of polymorphic Forms I and II of (S)-afoxolaner describedherein. In certain embodiments, bioequivalence between two crystal formsrefers to crystal forms having substantially similar bioavailability,substantially similar efficacy, substantially similar safety profiles,or a combination thereof.

In yet other embodiments, bioequivalence refers to crystal forms thatexhibit substantially similar pharmacokinetic profiles or therapeuticeffects. Bioequivalence may be demonstrated through several in vivo andin vitro methods. These methods may include, for example,pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In someembodiments, bioequivalence can be demonstrated using any suitablepharmacokinetic measures or combination of pharmacokinetic measuresknown in the art, including loading dose, steady-state dose, initial orsteady-state concentration of drug, biological half-life, eliminationrate, area under the curve (AUC), clearance, the peak blood or plasmaconcentration (C), time to peak concentration (T), bioavailability andpotency. In some embodiments, bioequivalence is achieved with similardosing amounts. In alternative embodiments, bioequivalence is achievedwith different dosing amounts.

In view of the pharmaceutical value of crystalline (S)-afoxolaner, ithas been important to be able to obtain it by an effective synthesisprocess that is readily scalable and that results in crystalline(S)-afoxolaner in a good yield and with excellent enantiomeric purityand chemical purity.

The Applicant has now developed a new synthesis process that results, ina reproducible manner and without the need for laborious purification,in crystalline (S)-afoxolaner of a purity compatible with its use as apharmaceutical active ingredient.

The examples are presented to further illustrate and explain the presentinvention and should not be taken as limiting in any regard. Unlessotherwise indicated in the examples and elsewhere in the specificationand claims, all parts and percentages are by weight. Temperatures are indegrees Centigrade.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Benefits, other advantages, and solutions to problems have beendescribed above with regard to specific embodiments. However, thebenefits, advantages, solutions to problems, and any feature(s) that maycause any benefit, advantage, or solution to occur or become morepronounced are not to be construed as a critical, required, or essentialfeature of any or all the claims.

It is noted that the invention does not intend to encompass within thescope of the invention any previously disclosed composition, product,process of making the product or method of using the product, whichmeets the written description and enablement requirements of the USPTO(35 U.S.C. 112, first paragraph) or the EPO (Article 83 of the EPC),such that applicant(s) reserve the right and hereby disclose adisclaimer of any previously described product, method of making theproduct or process of using the product.

EXAMPLES Example 1: Synthesis of Racemic Afoxolaner and (S)-Afoxolaner

Racemic afoxolaner can be obtained by a process such as that disclosedby U.S. Pat. No. 8,410,153, which is incorporated herein by reference inits entirety. Enantiomerically enriched afoxolaner enriched in the(S)-enantiomer can be obtained by a process such as that disclosed byU.S. Application No. 62/319,207, which is the priority document for U.S.Ser. No. 15/480,316 published as US 2017/0311601 A1, all incorporatedherein by reference in its entirety.

Example 2—Synthesis of Crystalline Toluene Solvate of (S)-Afoxolaner (a)Synthesis of (S)-Afoxolaner

-   -   1. 1 kilogram of compound (IIA-I) (1 eq.) and 9 volumes of        dichloromethane (DCM) are charged to a reactor and stirred to        dissolve the compound.    -   2. The mixture is cooled to about 0° C. and 50 grams (5% by wt.        of compound (IIA-I)) of the chiral phase transfer catalyst        (IIIa-13-1) and 1 liter of DCM are charged and the resulting        mixture is cooled to about −13° C.    -   3. A solution of 19% (w/w) hydroxylamine sulfate (294 g, 1.1        eq.) (made with 294 grams of (NH₂OH)H₂SO₄ and 141 grams of NaCl        in 1112 mL of water) and 4.4 equivalents of NaOH as a 17.6%        (w/w) solution (286 grams NaOH and 158 grams of NaCl in 1180 mL        water) are charged to the reaction mixture simultaneously.    -   4. The resulting reaction mixture was vigorously mixed about 20        hours at about −13° C. and then checked for reaction conversion        by HPLC (target ≤0.5% by area);    -   5. After completion of the reaction, water (3 vol.) was added at        about 0° C. Then, a solution of 709 g of KH₂PO₄ in 4.2 liters of        water are added to the mixture to adjust the pH (target 7-8) and        the resulting mixture is stirred at about 20° C. for 30 minutes.    -   6. The layers are allowed to settle, the aqueous layer is        removed and the organic layer is washed with 3 liters of water        twice to afford (S)-afoxolaner in the organic layer.

b) Crystallization of Toluene Solvate

-   -   1. After the extraction/washing step in Example 2(a)(6) above,        the dichloromethane is removed by distillation under vacuum to        about 1-2 volumes and toluene (about 5-10 volumes) is added.    -   2. The volume is adjusted by further distillation under vacuum        and/or addition of more toluene to about 5-6 volumes. The        mixture is distilled further while maintaining the volume to        largely remove the dichloromethane reaction solvent.    -   3. The mixture is then cooled to about 10° C. and seeded with        afoxolaner (racemic compound) and stirred at the same        temperature for at least 2 hours;    -   4. The mixture is heated to about 55-65° C., and aged (in one        embodiment for at least 17 hours) and then the solid racemate is        filtered off. The filtered solid is washed with toluene;    -   5. The combined filtrate and wash is adjusted to a volume of        about 5-6 volumes by distillation under vacuum and/or toluene        addition;    -   6. The resulting mixture is cooled to about 10° C. and aged for        at least 5 hours then filtered. The cake is washed with toluene.    -   7. The cake is dried at 50° C. under vacuum to obtain a        crystalline toluene solvate of (S)-Afoxolaner, as rod like        crystals.

Example 3: Formation of Crystalline Form I of (S)-Afoxolaner fromEthanol/Cyclohexane

In a 25 L jacketed vessel at 20° C. was added the following materials:

(S)-afoxolaner toluene solvate (e.e. 96%) 591 g EtOH (Ethanol) 709 mlCyclohexane 1773 ml

After addition of the materials, the reaction mixture was heated toabout 60° C. at a rate of 20° C./h and stirred. The rate of heating isnot essential and is dependent on the equipment used. After about onehour, an additional 6.4 L of cyclohexane was added and the stirringspeed adjusted to 100 rpm (0.04 W.L-1) and cool to 55° C. The mixturemay be seeded at this stage to aid with crystal formation. The mixturethen underwent the following sequence of steps twice:

Cooled to 30° C. (−10° C./h)

Stirred at 30° C. for 30 min

The stirring power was increased to 0.13 W.L-1

Heated to 60° C. (15° C./h)

Stir at 60° C. for 1 h

After the second sequence was completed, the mixture was cooled mixtureto 10° C. at a rate of −5° C./h and stirred for 5 h minimum at 10° C.The suspension was then filtered at 10° C. and washed twice at 10° C.with cyclohexane (i.e. 2×1.2 L). The filtered crystals were then driedunder vacuum (50 mbar) at 50° C. for 20 h to afford 453.7 g ofnon-solvated crystalline (S)-afoxolaner with a chemical purity greaterthan 94%, (e.e. ≥96%). Thermographic analysis (TGA) showed no weightloss to indicate the presence of a solvate crystalline form. Thenon-solvated crystalline (S)-afoxolaner was determined to be Form I byXRPD.

Example 4: Formation of Crystalline Form II of (S)-Afoxolaner fromEthanol/Cyclohexane

Using a process similar to Example 3 but using 100% optically pure(S)-afoxolaner toluene solvate and 15/85% v/v of ethanol to cyclohexaneas the crystallization solvent, afforded Form II of (S)-afoxolaner.Thermographic analysis (TGA) showed no weight loss to indicate thepresence of a solvate crystalline form. The non-solvated crystalline(S)-afoxolaner was determined to be Form II by XRPD.

X-Ray Powder Diffraction (XRPD) Analysis of (S)-Afoxolaner Forms I andII

TABLE 1 summarizes the peaks in the X-ray Diffraction Patterns of(S)-afoxolaner Forms I and II, measured using the following apparatusand parameters:

Apparatus: Bruker D8 Advance diffractometer

Source CuKa1 1=1.5406 Å; CuKa2 12=1.54436 Å

Generator: 40 kV-30 mA

Detector: lynx Eye.

PMMA sample holder

Phi spinner:

-   -   Rotation speed: 30 rpm    -   Angle range: 2° to 40° in theta-theta

Variable divergence slit: 12 mm (V12)

Step size: 0.02°

Step time 10.6 s

-   Form I shows the most prominent peaks at 2θ=10.03°, 10.48°, 13.16°,    15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52°, and    28.13°. By contrast, Form II shows the most prominent peaks at    2θ=5.99°, 12.99°, 15.80°, 18.71°, 19.33°, 20.24°, 21.65°, 22.17°,    26.11°, 29°.

TABLE 1 Form I XRPD peak list Form II XRPD peak list Peak Angle D valueIntensity I/Imax Peak Angle D value Intensity I/Imax No (2θ) (Å) (I) (%)No (2θ) (Å) (I) (%) 1 5.02 17.576 187 2.9 1 5.99 14.7493 3182 43.7 25.87 15.045 513 8.0 2 10.08 8.7712 995 13.7 3 6.07 14.560 656 10.3 310.51 8.4084 1717 23.6 4 10.03 8.810 1725 27.0 4 11.97 7.3855 1513 20.85 10.48 8.437 1776 27.8 5 12.99 6.8089 4067 55.8 6 11.74 7.532 348 5.4 613.51 6.5508 506 6.9 7 12.16 7.273 790 12.4 7 15.80 5.6046 7286 100 813.16 6.723 1635 25.6 8 16.29 5.4384 693 9.5 9 13.57 6.520 363 5.7 917.63 5.0263 1338 18.4 10 15.42 5.742 1003 15.7 10 18.00 4.9236 126017.3 11 15.80 5.604 3492 54.6 11 18.44 4.8071 884 12.1 12 16.07 5.5112125 33.2 12 18.71 4.7400 1618 22.2 13 17.65 5.021 3249 50.8 13 19.334.5872 2761 37.9 14 18.29 4.847 643 10.1 14 20.24 4.3843 4113 56.5 1519.00 4.668 1558 24.4 15 20.67 4.2943 2805 38.5 16 19.44 4.563 1635 25.616 21.09 4.2099 1317 18.1 17 20.16 4.400 6394 100 17 21.65 4.1013 578879.4 18 20.90 4.246 1830 28.6 18 22.17 4.0068 6022 82.7 19 21.50 4.1291010 15.8 19 23.11 3.8462 1007 13.8 20 22.15 4.010 4327 67.7 20 23.583.7702 2753 37.8 21 23.04 3.857 991 15.5 21 24.07 3.6944 1037 14.2 2223.68 3.754 2089 32.7 22 24.62 3.6137 2338 32.1 23 24.66 3.608 1298 20.323 25.19 3.5321 1035 14.2 24 25.04 3.553 2004 31.3 24 25.60 3.4766 85711.8 25 25.34 3.511 1379 21.6 25 26.11 3.4098 5723 78.5 26 26.09 3.4121195 18.7 26 26.93 3.3080 915 12.6 27 26.33 3.382 1489 23.3 27 27.193.2776 1137 15.6 28 26.52 3.358 1774 27.7 28 27.67 3.2218 734 10.1 2926.92 3.309 1162 18.2 29 28.12 3.1705 1466 20.1 30 27.38 3.254 732 11.430 29.00 3.0761 3663 50.3 31 28.13 3.169 1596 25.0 31 29.57 3.0187 127117.4 32 28.88 3.089 781 12.2 32 30.22 2.9555 2397 32.9 33 29.55 3.0201305 20.4 33 30.67 2.9130 872 12 34 30.77 2.904 1210 18.9 34 31.242.8611 790 10.8

Differential Scanning Calorimetry Thrmogram Analysis of (S)-afoxolanerForms I and II

Form I and Form II were measured using the following apparatus andparameters:

Apparatus: PerkinElmer Diamond DSC

Atmosphere: Nitrogen 20 ml/min

Pan: 50 μl Aluminium pan

Lid: perforated Aluminium lid with 100 μm hole

Rate: 5° C./min

Form I: differential scanning calorimetry (DSC) thermogram having a peakat a temperature of about 146° C., and an onset at about 143° C.

Form II: differential scanning calorimetry (DSC) thermogram having apeak at a temperature of about 149° C., and an onset at about 146° C.

Example 5: Formation of the Crystalline Form I of (S)-Afoxolaner fromEthyl Acetate

Following the procedure of Example 3, but using Ethyl Acetate ratherthan EtOH/Cyclohexane mixture and after the second sequence wascompleted, the mixture was cooled to 4° C. at a rate of −5° C./h andstirred for 72 h at 4° C., the crystalline Form I of (S)-afoxolaner wasisolated.

Example 6: Formation of the Crystalline Form I of (S)-Afoxolaner fromAcetonitrile

Following the procedure of Example 3, but using Acetonitrile rather thanEtOH/Cyclohexane mixture, and after the second sequence was completed,the mixture was cooled mixture to 4° C. at a rate of −5° C./h andstirred for 72 h at 4° C., the crystalline Form I of (S)-afoxolaner wasisolated.

What is claimed is:
 1. A crystalline compound of formula (Ia),designated as Form I,

wherein said crystals are characterized by having an x-ray powderdiffraction pattern comprising three, four, five, six, seven or morepeaks selected from the group consisting of: 10.03°, 10.48°, 13.16°,15.42°, 15.80°, 16.07°, 17.65°, 20.16°, 22.15°, 23.68°, 26.52°, and28.13° 2θ±0.2 as determined on a diffractometer using Cu-Kα radiation.2. The crystalline compound of formula (Ia) according to claim 1,characterized by having an x-ray powder diffraction pattern comprisingthree or more peaks selected from the group consisting of: 10.03°,10.48°, 13.16°, 20.16°, and 22.15° 2θ±0.2 as determined on adiffractometer using Cu-Kα radiation.
 3. The crystalline compound offormula (Ia) according to claim 1 or 2, characterized by having an x-raypowder diffraction pattern substantially similar to FIG.
 1. 4. Thecrystalline compound of formula (Ia) according to any one of claims 1 to3, characterized by having a differential scanning calorimetry (DSC)thermogram having an peak at a temperature of about 146° C., and anonset at about 143° C., measured with the heating rate of 5° C./min. 5.The crystalline compound of formula (Ia) according to any one of claims1 to 4, characterized by having a differential scanning calorimetry(DSC) thermogram having a heat of fusion of about 61.7 J/g.
 6. Thecrystalline compound of formula (Ia) according to any one of claims 1 to5, characterized by having a differential scanning calorimetrythermogram substantially similar to FIG.
 2. 7. The crystalline compoundof formula (Ia) according to any one of claims 1 to 6, which isenantiomerically pure.
 8. The crystalline compound of formula (Ia)according to any one of claims 1 to 7, having a degree of chemicalpurity of at least 97%.
 9. The crystalline compound of formula (Ia)according to any one of claims 1 to 8, having an enantiomeric purity ofat least 98%.
 10. The crystalline compound of formula (Ia) according toany one of claims 1 to 9, in substantially pure crystal form.
 11. Acrystalline compound of formula (Ia), designated as Form II,

wherein said crystals are characterized by having an x-ray powderdiffraction pattern comprising three, four, five, six, seven or morepeaks selected from the group consisting of: 5.99°, 12.99°, 15.80°,18.71°, 19.33°, 20.24°, 21.65°, 22.17°, 26.11° and 29.00° 2θ±0.2 asdetermined on a diffractometer using Cu-Kα radiation.
 12. Thecrystalline compound of formula (Ia) according to claim 11, wherein saidcrystals are characterized by having an x-ray powder diffraction patterncomprising three or more peaks selected from the group consisting of:5.99°, 12.99°, 15.80°, 22.17°, 26.11° 2θ±0.2 as determined on adiffractometer using Cu-Kα radiation.
 13. The crystalline compound offormula (Ia) according to claim 11 or 12, characterized by having anx-ray powder diffraction pattern substantially similar to FIG.
 3. 14.The crystalline compound of formula (Ia) according to any one of claims11 to 13, characterized by having a differential scanning calorimetry(DSC) thermogram having an peak at a temperature of about 149° C., andan onset at about 146° C., measured with the heating rate of 5° C./min.15. The crystalline compound of formula (Ia) according to any one ofclaims 11 to 14, characterized by having a differential scanningcalorimetry (DSC) thermogram having a heat of fusion about 65.7 J/g. 16.The crystalline compound of formula (Ia) according to any one of claims11 to 16, characterized by having a differential scanning calorimetrythermogram substantially similar to FIG.
 4. 17. The crystalline compoundof formula (Ia) according to any one of claims 11 to 16, which isenantiomerically pure.
 18. The crystalline compound of formula (Ia)according to any one of claims 11 to 17, having a degree of chemicalpurity of at least 97%.
 19. The crystalline compound of formula (Ia)according to any one of claims 1 to 9 or 11 to 18, wherein the compoundof formula (Ia) is a mixture of crystalline Form I with a crystallineForm II and/or an amorphous form of the compound of formula (Ia).
 20. Apharmaceutical composition comprising the crystalline compound offormula (Ia) Form I according to any one of claims 1 to 10 and/or thecrystalline compound of formula (Ia) Form II according to any one ofclaims 11 to 18, and at least one pharmaceutically acceptable excipient.21. The composition according to claim 20, wherein the compositioncomprises a mixture of the crystalline compound of formula (Ia) Form Iand/or Form II and/or an amorphous form of the compound of formula (Ia).22. The pharmaceutical composition of claim 21, wherein the compositioncomprises at least 90% by weight of the crystalline compound of formula(Ia) Form I according to any one of claims 1 to 10 or at least 90% byweight of the crystalline compound of formula (Ia) Form II according toany one of claims 11 to 18, based on the total weight of compound offormula (Ia) in the composition.
 23. A process for preparing acrystalline compound of formula (Ia) according to any one of claims 1 to10 or any one of claims 11 to 19, which comprises:— (a) heating amixture of the toluene solvate of (S)-afoxolaner in a solvent, whereinthe solvent is acetonitrile, ethyl acetate, a linear, branched or cyclicaliphatic solvent or an alcohol, or a mixture thereof, until dissolutionhas occurred; (b) reducing the temperature of the solvent system toinduce nucleation; (c) maintaining the mixture at a temperature belowthat at which nucleation has commenced; and (d) isolating thecrystalline compound of formula (Ia) so deposited.
 24. The processaccording to claim 23 wherein the alcohol is a lower alkyl alcohol. 25.The process according to claim 24 wherein the lower alkyl alcohol isethanol.
 26. The process according to any one of claims 23 to 25,wherein the aliphatic solvent is a linear, branched or cyclic alkanesolvent.
 27. The process of any one of claims 23 to 26 wherein thesolvent is a mixture comprising ethanol and cyclohexane.
 28. The processof claim 27 wherein the mixture of ethanol and cyclohexane is about 3:97to about 10:90 (v/v) ethanol to cyclohexane.
 29. The process of claim 27or 28 wherein the mixture of ethanol and cyclohexane is about 8:92 (v/v)ethanol to cyclohexane.
 30. The process of any one of claims 23 to 29comprising seeding with enantiomerically pure (S)-afoxolaner Form I. 31.The process of any one of claims 23 to 30, wherein the heating is toabout 50 to about 80 degrees Celsius.
 32. The process of any one ofclaims 23 to 31, wherein reducing the temperature is to a temperature ofabout 5 degree Celsius.
 33. A crystalline form of (S)-afoxolanerproduced by the process of any one of claims 23 to
 32. 34. A method fortreating or preventing parasitic infestation in an animal comprisingadministering to the animal an effective amount of crystalline compoundof formula (Ia) Form I according to any one of claims 1 to 10 or acrystalline compound of form (Ia) Form II according to any one of claims11-18, or a pharmaceutical composition according to any one of claims20-22.